The aim of this study was to optimize the extraction of antioxidant compounds from Schinus areira leaves using ultrasound assisted extraction and response surface methodology. The effect of sonication time and plant material:solvent ratio were used to optimize the recovery. Results showed that a high recovery of antioxidant compounds from leaves of three different S. areira specimens was achieved under optimized conditions. The leaf extracts obtained displayed a DPPH (1,1-Diphenyl-2-picrylhydrazyl) radical scavenging activity analogous to the well-known antioxidant trolox (EC50 = 23-46 vs 36.1 µg/mL, respectively). In addition, these extracts showed a good potency to eliminate superoxide and nitric oxide-radicals as well as a moderate antimicrobial activity against gram positive Staphylococcus aureus and Enterococcus faecalis and yeast. HPLC chromatography analysis of the three S. areira leaf extracts showed different high contents of kaempferol-3-O-rutinoside, quercetin-3-O-galactoside and 3-O-caffeoylquinic acid. The results showed that the S. areira leaf extracts contained a high amount of antioxidant phenolic compounds, which might be a valuable source to be used as additives in plant-based foods.